1. Field of the Invention
The invention is related to a method of treating a neurodegenerative disease, such as, for example, Parkinson's Disease.
2. Description of Related Art
Parkinson's Disease is a progressive neurodegenerative disorder characterized by any combination of slowness of movement (bradykinesia), tremors, exaggerated movements from excess dopamine (dyskinesia), muscle-stiffness, freezing in place while attempting to walk (akinesia), and a progressive loss of cognition. Current treatment standard for Parkinson's Disease is SINEMET® 25/100, a carbidopa (25 mg)/levodopa (100 mg) tablet (Merck & Co.), available in standard (STD) and controlled-release (CR) forms. Although SINEMET® helps improve movement, it does little to aid the decline in cognition; thus other treatments are needed to slow both the decline in movement and cognition.
Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid. The plasma half-life of levodopa is about 50 minutes, without carbidopa. When carbidopa and levodopa are administered together, the half-life of levodopa is increased to about 1.5 hours. At steady state, the bioavailability of carbidopa from SINEMET® tablets is approximately 99% relative to the concomitant administration of carbidopa and levodopa.
SINEMET® is an immediate-release formulation of carbidopa-levodopa that is designed to begin release of ingredients within 30 minutes; thus the drug should be taken at regular intervals according to the schedule outlined by the physician.
One of the side effects reported with SINEMET® is a sudden onset of sleep during daily activities, in some cases without awareness or warning signs, when they are taking dopaminergic agents, including levodopa. Thus, patients should be advised to exercise caution while driving or operating machinery and that if they have experienced somnolence and/or sudden sleep onset, they must refrain from these activities. Further, there have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges, including hoarding, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's Disease, including SINEMET®.
Co-administration of SINEMET® with other drugs could also lead to undesirable side-effects. For example, symptomatic postural hypotension occurred when SINEMET® was added to the treatment of a patient receiving antihypertensive drugs. Therefore, SINEMET® therapy may require dosage adjustment of the antihypertensive drug. Importantly, nonselective monoamine oxidase (MAO) inhibitors (Type A or B) are contraindicated for use with SINEMET®. The SINEMET® package insert states that these inhibitors should be discontinued at least two weeks prior to initiating therapy with SINEMET®. SINEMET®, however, may be administered concomitantly with the manufacturer's recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline hydrochloride).
Other currently available options for treating patients with Parkinson's Disease include monoamine oxidase B (MAO-B) inhibitors rasagiline (AZILECTt®) and selegiline (ELDEPRYL®). Rasagiline and selegiline, alone or in combination with other medications, are frequently the first course of Parkinson's Disease therapy prior to starting SINEMET® because they have been shown to delay the appearance of SINEMET® (levodopa)-induced dyskinesias (The Parkinson Study Group, Arch. Neurol. 2002; Parkinson Study Group, Arch. Neurol., 1989).
Selegiline, but not rasagiline, was shown to provide neuroprotective effects based on its ability to delay the emergence of disability and the progression of motor symptoms in comparison with a placebo (Parkinson Study Group, N. Engl. J. Med., 1989). Selegiline neuroprotection is believed to result from the upregulation of antioxidant and anti-apoptotic molecules such as glutathione, superoxide dismutase (SOD), and BCL-2 (Mytilineou, et al., J. Pharmacol. Exp. Ther., 1998; Tatton, et al., J. Neurochem., 1994; Tatton, et al., Neurodegeneration and Neuroprotection in Parkinson's Disease, 1996). However, concomitant therapy with selegiline and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone. As the dose of selegiline is increased, its selectivity to inhibit only MAO-B decreases and MAO-A inhibition may also occur. (Hauser, et al., 2003); Goetz, et al., Mov. Disord., 2002; Goetz, et al. Mov. Disord., 2005)
Resveratrol is a common name for 3,5,4′-trihydroxy-stilbene, which exists as two geometric isomers: cis- (Z) and trans- (E). Resveratrol is found to be most concentrated in the skins of red grapes (Creasey, et al., J Am Soc Hortic Sci, 1988) and has been shown to decrease plaque formation in Alzheimer's mouse brain (Karruppagounder, et al., Neurochemistry International, 2009), to activate the Sir 2 sirtuin gene (whose homolog in mammals is known as SIRT1), which promotes longevity (Wood, et al., Nature, 2004), and to be neuroprotective in neurodegeneration models in Alzheimer's Disease and Amyotrophic Lateral Sclerosis, (Kim, et al., EMBO J., 2007), as well as other studies, (Anekonda, et al., Brain Research Reviews, 2006; Sharma, et al., Life Sciences, 2002; Kumar, et al., Behavioral Pharmacology, 2006; Yang, et al., Acta Pharmacologica Sinica, 2003; Sinha, et al., Life Sciences, 2002). The recent finding that Alzheimer's disease and Parkinson's Disease genes reside on a common locus is a further indication that resveratrol is likely to be of benefit to both diseases (Li, et al., Hum. Mol. Genet., 2008).
In studies of rat brain, trans-resveratrol, 3,5,4′-trihydroxy-trans-stilbene (t-RES) was shown to inhibit monoamine oxidase A (MAO-A) slightly more than MAO-B, with t-RES inhibiting both MAOs more than cis-resveratrol (c-RES) indicating that resveratrol has a similar chemical structure to some antidepressants (Yáñez, et al., Biochem. Biophys. Res. Commun., 2006).
Although, about 70% of the resveratrol dose given orally as a pill is absorbed, oral bioavailability of resveratrol is low because it is rapidly metabolized in intestines and liver into conjugated forms: glucuronate and sulfonate (Walle, et al., Drug Metabolism and Disposition, 2004). Only trace amounts (below 5 ng/mL) of unchanged resveratrol could be detected in the blood after 25 mg oral dose (LaPorte, et al., Clinical Pharmacokinetics, 2010).
Full formal pharmacokinetics of oral resveratrol 2000 mg taken twice daily in humans, studying the interaction with concurrent ethanol, quercetin and a fatty meal has been reported (LaPorte, et al., Clinical Pharmacokinetics, 2010). Mean peak serum resveratrol concentration was 1274 ng/mL at steady-state, which was reduced 46% by a fatty meal at dosing. There was no effect of concurrent oral quercetin or ethanol. Healthy volunteers given resveratrol had frequently reported minor diarrhea, and laboratory measures identified slight changes in liver function tests and serum potassium. No adverse effect on renal function was identified, although only eight healthy adults were observed in the two-week study. A small study showed no adverse effects of up to 5 g of resveratrol in healthy volunteers (Boocock, et al, Cancer Epidemiology, Biomarkers & Prevention, 2007).
Less than 5% of the oral dose is being observed as free resveratrol in blood plasma in humans (Boocock, et al., Cancer Epidemiology, Biomarkers & Prevention, 2007; Walle, et al., Drug Metabolism and Disposition, 2004) and rats (Marier, et al., The Journal of Pharmacology and Experimental Therapeutics, 2002; Abd El-Mohsen, et al., The British Journal of Nutrition, 2006; Wenzel, et al., Molecular Nutrition & Food Research, 2005.) The most abundant resveratrol metabolites in humans, rats, and mice are trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate (Yu, et al., Pharmaceutical Research, 2002). Walle et al. suggests sulfate conjugates are the primary source of activity (Drug Metabolism and Disposition, 2004), Wang et al. suggests the glucuronides, Wang, et al., Journal of Pharmaceutical Sciences, 2004) and Boocock et al. also emphasized the need for further study of the effects of the metabolites, including the possibility of deconjugation to free resveratrol inside cells.
A formulation of resveratrol in a chewing gum form is now in production, and this would be expected to achieve much higher blood levels than oral formulations. Resveratrol given in a proprietary formulation SRT501 (3 or 5 g), developed by Sirtris Pharmaceuticals, reached five to eight times higher blood levels. These levels did approach the concentration necessary to exert the effects shown in animal models and in vitro experiments (Elliott, et al., Current Opinion in Investigational Drugs, 2008). However, clinical trials were terminated due to kidney failure in some patients in December 2010 [ClinicalTrials.gov Identifier: NCT00920556].
Other more bioavailable SIRT1 activators, SRT2104 and SRT2379 are currently being tested in exploratory clinical trials (ClinicalTrials.gov Identifiers: [NCT00920660] and [NCT01262911]
In contrast, no studies have been carried out to date evaluating effectiveness and tolerability of the “less bioavailable” or naturally occurring form of t-RES in ameliorating the symptoms of Parkinson's Disease even at relatively high concentrations.
Accordingly, the inventor has identified a need in the art to provide a method for testing a therapeutic benefit such as, for example, improving the pharmacokinetics of SINEMET® making it more potent and longer-lasting, and potential anticoagulant risks of t-RES supplements in patients with Parkinson's Disease, a method for treating a neurodegenerative disease, and a method for reducing alpha-synuclein amyloid proteins in a patient suffering from Parkinson's Disease.